US9169261B2ActiveUtilityPatentIndex 92
CXCR7 antagonists
Est. expiryNov 29, 2032(~6.4 yrs left)· nominal 20-yr term from priority
Inventors:FAN JUNFAKRASINSKI ANTONILANGE CHRISTOPHER WLUI REBECCA MMCMAHON JEFFREY PPOWERS JAY PZENG YIBINZHANG PENGLIE
A61P 35/00A61P 43/00A61P 29/00A61P 25/00G01N 33/5759A61K 51/0459C07D 487/04G01N 2333/7158A61K 31/519
92
PatentIndex Score
13
Cited by
14
References
26
Claims
Abstract
Compounds having formula I, or pharmaceutically acceptable salts, hydrates or N-oxides thereof are provided and are useful for binding to CXCR7, and treating diseases that are dependent, at least in part, on CXCR7 activity. Accordingly, the present invention provides in further aspects, compositions containing one or more of the above-noted compounds in admixture with a pharmaceutically acceptable excipient.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound having formula I
or a pharmaceutically acceptable salt, hydrate, N-oxide, isotopically enriched or enantiomerically enriched version or a rotamer thereof, wherein
each of ring vertices X a , X b and X c is independently selected from the group consisting of N, NH, N(R 2 ), O, CH and C(R 2 );
the subscript n is 0, 1 or 2;
Z is selected from the group consisting of
(i) monocyclic or fused-bicyclic aryl and heteroaryl, wherein the heteroaryl group has from 1-4 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 5 R 5 substituents;
(ii) monocyclic four-, five-, six- or seven-membered ring selected from the group consisting of cycloalkane, and heterocycloalkane, wherein the heterocycloalkane rings have from 1-3 heteroatoms as ring members selected from N, O and S; and wherein each of said monocyclic Z rings are optionally substituted with from 1 to 3 R 5 substituents;
R 1 is a member selected from the group consisting of H and C 1-8 alkyl, wherein the alkyl portion is optionally substituted with halogen, —NR a R b , —OR a , —CO 2 R a , and —CONR a R b ;
each R 2 is independently selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —X—CO 2 R a , —NR a R b , —CONR a R b and —X—CONR a R b ;
R 3 is a member selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —CO 2 R a , —X—CO 2 R a , —CONR a R b and —X—CONR a R b ;
each R 4 , when present, is a member independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —X—CO 2 R a , —NR a R b , —CONR a R b and —X—CONR a R b ;
each R 5 is a member independently selected from the group consisting of halogen, CN, —X—CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-5 spirocycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8
hydroxyalkyl, —OR a , —CO 2 R a , —X—CO 2 R a , —NR a R b , —CONR a R b , —X—CONR a R b , aryl, 5- or 6-membered heteroaryl, and 3-, 4-, 5- or 6-membered heterocyclic wherein the heteroatoms present as ring vertices of the heteroaryl and heterocyclic rings are selected from N, O and S, and wherein the aryl, heteroaryl and hetereocyclic portions of R 5 are optionally further substituted with 1-3 R a ;
each R a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylalkyl, amino, C 1-8 alkylamino, di C 1-8 alkylamino, carboxamide, carboxy C 1-4 alkyl ester, carboxylic acid, and —SO 2 — C 1-8 alkyl;
each X is a C 1-4 alkylene linking group or a linking group having the formula —(CH 2 ) m O(CH 2 ) p —, wherein the subscripts m and p are integer of from 0 to 5, and m+p is from 0 to 6, wherein any of the methylene portions of X are optionally substituted with one or two methyl groups.
2. The compound of claim 1 , wherein Z is monocyclic or fused-bicyclic heteroaryl, having 1-3 heteroatoms as ring members selected from N, O and S; and wherein said heteroaryl group is optionally substituted with from 1 to 5 R 5 substituents.
3. The compound of claim 2 , wherein n is 0.
4. The compound of claim 3 , wherein R 1 is H.
5. The compound of claim 1 , wherein Z is monocyclic or fused-bicyclic heteroaryl selected from the group consisting of imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiazole, oxazole, oxadiazole, pyrimidine, pyrazine, pyridazine, and quinazoline, each of which is optionally substituted with from 1-2 R 5 substituents.
6. The compound of claim 1 , wherein each R 2 is independently selected from the group consisting of H and C 1-4 alkyl.
7. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, CH 2 OH and C(O)NH 2 .
8. The compound of claim 1 , having the structure:
9. The compound of claim 8 , wherein the bicyclic portion having X a , X b and X c as ring vertices is selected from the group consisting of:
10. A compound of claim 8 , wherein Z is a 5-membered heteroaryl group substituted with one R 5 group selected from an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring, and optionally with up to two additional R 5 groups which are selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl and CH 2 CN.
11. A compound of claim 10 , wherein Z is selected from the group consisting of:
12. The compound of claim 8 , wherein Z has the formula:
wherein each Q is independently selected from the group consisting of N, CH, and C(R 5 ).
13. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 , wherein R a is selected from the group consisting of hydrogen, halogen, cyano, C 1-8 alkyl and —SO 2 — C 1-8 alkyl.
15. The compound of claim 13 , wherein R 2 is selected from the group consisting of H and C 1-4 alkyl.
16. The compound of claim 13 , wherein R a is selected from the group consisting of hydrogen, halogen, cyano, C 1-8 alkyl and —SO 2 — C 1-8 alkyl; and R 2 is selected from the group consisting of H and C 1-4 alkyl.
17. The compound of claim 1 , is selected from the group consisting of:
18. The pharmaceutical composition comprising a compound of claim 17 .
19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
20. A method of treating a disease or disorder in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1 , for a period of time sufficient to treat said disease or disorder wherein said subject is a mammal.
21. The method of claim 20 , wherein the compound is a compound of claim 17 .
22. The method of claim 20 , wherein said disease or disorder is selected from the group consisting of cancer, inflammation and neural or progenitor/stem cell disorders.
23. A method for imaging a tumor, organ, or tissue, said method comprising:
(a) administering to a subject in need of such imaging, a radiolabeled or detectable form of a compound of any of claim 1 ; and
(b) detecting said compound to determine where said compound is concentrated in said subject.
24. A method in accordance with claim 23 , wherein said compound is radiolabeled.
25. A compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt, hydrate, N-oxide, isotopically enriched or enantiomerically enriched version or a rotamer thereof
26. A compound of claim 1 , having the formula:Cited by (0)
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